Cystic fibrosis drug ivacaftor offers patients new hope

Amina Khan, Los Angeles Times

All her life, Lindsay Shipp knew that she was dying. As a baby, she would cry after eating, and salt collected on her forehead. The diagnosis was cystic fibrosis, an incurable genetic disease that, at the time, meant a life expectancy of 18 years.

The disease, which affects 30,000 people in the United States, hinders the movement of salt in the body. Because of this, the pancreas fails soon after birth, patients cannot properly digest food, and their airways fill with mucus, leaving them vulnerable to lung infections and other problems. The current average life expectancy is now 37.

"I had this race-against-time mentality where I did everything I could possibly do in a day," said Shipp, now 27 and working part time in San Diego as a bookkeeper and at an Apple store. "I never let a moment go to waste."

Shipp starred in her high school musicals and dreamed of auditioning on Broadway, until her lungs got so bad that she gave up singing and dancing.

But since she started taking an experimental drug as part of a closely watched clinical trial, her outlook has changed. The drug, called ivacaftor, cleared her lungs and allowed her to add a healthy 15 pounds to her 5-foot, 100-pound frame. On the day in February of last yearwhen a regular checkup revealed her lungs were functioning at 96% — bringing her to essentially the same level as a healthy person — Shipp collapsed on a bench outside the hospital and sobbed with relief. "I realized I would have a full life at that moment," she said.

The trial results, published in Thursday's edition of the New England Journal of Medicine, showed that ivacaftor reduced the incidence of pulmonary exacerbations — sudden, serious flare-ups that can send patients to the hospital and cause irreversible lung damage — by 55% compared with a placebo. The study of 161 patients also found that patients who took the drug saw their lung function improve 10.4% and gained nearly 6 pounds over 48 weeks.

"This is exciting work," said Michael Welsh, a pulmonary physician at the University of Iowa who was not involved in the study. "I think that it is very promising for the people who have this particular mutation, and it may turn out to have broader significance."

Ivacaftor affects a genetic mutation in 4% to 5% of cystic fibrosis patients that prevents a protein called CFTR from allowing enough chloride ionsto exit a certain type of cell. Chloride, when coupled with sodium to make salt, helps regulate the flow of water in the body. When that channel doesn't work, the lungs dry up and the once-protective mucus grows thick and immovable, providing an ideal breeding ground for bacteria.

This salt imbalance affects the pancreas and digestive tract, so patients are often small and malnourished. The sweat glands don't work properly either, leading to overly salty skin.

The drug helps that chloride gateway stay open, restoring the salt balance in the body. It is the first therapy that fixes the basic problem that causes the disease, not just the symptoms, said study coauthor Michael Konstan, a pediatric pulmonologist at Case Western Reserve University School of Medicine in Cleveland.

"The goal is if you would give a therapy like this before [the lungs deteriorate], you can prevent lung disease from developing," Konstan said.

The drug can't yet help the vast majority of cystic fibrosis sufferers: About 90% of them have a mutation in which the protein, once manufactured inside the cell, never even makes it to the cell surface where it is supposed to act as a chloride channel. Researchers are trying to develop drugs that would help bring that protein to the surface. Once a patient is on such a drug, ivacaftor could then pick up the process from there.

"It's creating such a sense of hope and optimism for all the cystic fibrosis patients because this approach will work," said Robert Beall, president and chief executive of the Bethesda, Md.-based Cystic Fibrosis Foundation, which has spent millions funding such research.

Although therapies to fight the disease seemed to be around the corner when the CFTR gene was discovered in 1989, it took more than two decades to develop a treatment based on the genetic defect.

"This timeline suggests that much of the promise of the Human Genome Project has yet to be fulfilled and that realizing the therapeutic benefits will take persistence and determination," Dr. Pamela Davis of Case Western wrote in an editorial accompanying the study. "Society cannot allow support for research and development to be compromised in the current rush to cut the federal budget."

If all goes smoothly, ivacaftor may be approved by the Food and Drug Administration in 2012, said study lead author Bonnie Ramsey, a pediatric pulmonologist at Seattle Children's Hospital. The study was partially funded by ivacaftor's maker, Vertex Pharmaceuticals Inc. of Cambridge, Mass., which plans to market it under the name Kalydeco.

The drug is not an absolute cure. It cannot rid the body of bacterial infections that stick around even after mucus has been cleared from the lungs. But perhaps, if given to patients that were young enough — say, newborns — it could allow them to live an essentially normal life.

As for Lindsay Shipp, who will be singing at the Cystic Fibrosis Conference in Anaheim this week — a downtempo cover of Katy Perry's "Firework" and "Thank You for the Music," from the musical "Mamma Mia!" — the girl who once gave up her dreams of Broadway now thinks she might fly to New York and audition.

"It's like there's someone else's lungs inside of me," Shipp said. "It's awesome — I feel like I can do anything."